The overarching hypothesis of this proposal is that human subpopulations are acquiring mutational loads and thereby potentially are evolving at different rates. To test this hypothesis, one needs to study processes that have genome wide effects as opposed to those that only alter the expression of a single gene. Such a general, genomewide agent is the L1 retrotransposon. In this proposal, we determine the variation in L1 retrotransposition capability in the human population as a potential surrogate marker for genome-wide, evolutionary drive. Long Interspersed Nuclear Element-1 (LINE-1 or L1) is an abundant retrotransposon that comprises ~17% of human DNA. The vast majority of L1s are fossil relics and can no longer move (i.e., retrotranspose) because of inactivating mutations. We have determined that an individual human genome as represented by the human genome working draft (HGWD) contains roughly 80-100 active L1 retrotransposons, but that only about 6 account for 84% of the observed retrotransposition activity. On the other hand, we have found that "private" or genome-specific L1s are not uncommon, leading us to hypothesize that there are a very large number, perhaps millions, of highly active L1s in the total human gene pool and that the variation in L1 activity among individual human beings is substantial. This grant represents a logical extension of the work of two experienced groups in the field of human and mammalian retrotransposons in an effort to answer an important question in human biology. The groups bring important areas of technical expertise, namely, 1) a technique to display the human-specific L1s of any individual in a denaturing polyacrylamide gel, 2) a high throughput, rapid assay of the relative retrotransposition frequency of any L1 in tissue culture, and 3) high throughput methods to determine presence/absence polymorphisms of different L1s. Using these methods, we will measure the total variation in L1 retrotransposition capability among individuals by determining both presence/absence of various L1s and allelic variation in their retrotransposition capability. We will also determine the fraction of L1s active in the tissue culture assay that are transcribed in vivo. Using this data, we will determine the extent of variation in L1 retrotransposition capability that exists among different individuals and geographic groups.